Distinct molecular profiles characterize the spontaneous growth rate of IDHmt low-grade astrocytoma and oligodendroglioma, WHO grade 2

BackgroundThe life expectancy of patients with diffuse IDH-mutant low-grade gliomas (IDHmt LGG) WHO grade 2 ranges from 5 to over 20 years. Tumor behavior, including spontaneous growth rate, varies even within homogeneously classified subtypes of oligodendroglioma and astrocytoma. Risk-adjusted treatment strategies are needed to avoid therapy-related toxicities, without compromising outcome. The spontaneous tumor volume growth rate (TVGR) serves as a prognostic marker and predicts response to therapy. Accurate prediction of TVGR through biomarkers would enable an improved evidence-based risk management. Patients & MethodsA cohort of 77 patients treated in Montpellier, France, for IDHmt LGG grade 2 (29 oligodendrogliomas, 48 astrocytomas) was analyzed (age >18 years; MRI scans and frozen tumor tissue available). DNA methylome profiling (Illumina, EPIC array) and RNA sequencing were established. TVGR was determined based on serial MRI collected over the "watch & wait" period from diagnosis to first treatment beyond surgery. Transcriptomic and methylome data were analyzed for signatures associated with TVGR using rank-rank regression followed by preranked gene set enrichment analysis. ResultsThe median TVGR was lower in IDHmt codeleted compared to non-codeleted LGG, (0.241 year-1 range 0.082-0.366 vs 0.424 year-1 range 0.264-0.609, p<0.001). In codeleted IDHmt LGG, TVGR was associated with deregulated gene signatures for signal transduction, neuronal systems, growth factor stimulation, and neural progenitor- and stem cells. In contrast, TVGR in noncodeleted IDHmt LGG was associated predominantly with proliferation-related signatures. ConclusionSpontaneous TVGR of codeleted and non-codeleted IDHmt LGG involve distinct biological processes, suggesting possible differences in response to therapies. Key PointsO_LIIDHmt glioma WHO grade 2 growth rate impacts outcome and response to therapy C_LIO_LIMolecular drivers of spontaneous growth rates are distinct between astrocytomas and oligodendrogliomas C_LIO_LIPossible impact on treatment response and outcome C_LI Importance of StudyThe life expectancy of patients with diffuse IDH-mutant low-grade gliomas (IDHmt LGG) WHO grade 2 ranges from 5 to over 20 years, with tumor behavior and growth rate varying even within homogeneous histo-molecular subtypes. Risk-adapted treatment strategies are needed to avoid therapy-related toxicities, without compromising outcome. The spontaneous tumor volume growth rate (TVGR) is a prognostic marker and predicts therapy response. We analyzed a cohort of 77 patients with IDHmt LGG, with available MRI and tumor tissue. DNA methylome profiling and RNA sequencing were performed. TVGR was calculated from serial MRI during the "watch & wait" period before any treatment beyond surgery. TVGR in non-codeleted LGG patients was mainly associated with gene signatures linked with proliferation, while it was associated with deregulated gene signatures for signal transduction, neuronal systems, growth factor stimulation, and neural progenitors and stem cells in codeleted tumors. These insights suggest possible differences in response to therapies.